Pancreatic islet transplantation holds great promise for the treatment of type 1 diabetes; recent advances in islet isolation and immunosuppression have led to greatly improved results. However, major obstacles and gaps in our current scientific knowledge preclude islet transplantation from being widely adapted as a treatment for type 1 diabetes. For example, most patients require islets isolated from two pancreata to become insulin-independent and often insulin-independence is not permanent. Safe, clinically applicable approaches to increase or sustain islet mass after transplantation in humans are hampered by the inability to study islets or assess islet mass after transplantation in humans. Using a multidisciplinary approach and the transplantation of murine, non-human primate, and human islets, our team proposes to test the hypothesis that glucagon-like peptide-1 (GLP-1), a promising therapy for improving islet function in type 2 diabetes, will increase or sustain islet mass after transplantation. In response to the RFA, the proposed studies will progress from basic science studies in cultured islets and genetically modified mice (bench) to studies of islet transplantation in non-human primates (bedside). In the R-21 phase of the research, we propose the following specific aims: 1) Ascertain the physiological importance of GLP-1 R signaling in murine islet transplantation using genetically modified mice with increased or decreased GLP-1 action. 2) Determine if GLP-1 administration before and/or after transplantation improves the survival of non-human primate islets into an immunodeficient mouse model that allows for in vivo study of xenotransplanted human islets. If these results are informative, we propose a R-33 phase with the following specific aims: 1) Determine the optimal parameters for GLP-1 administration using non-human primate and human islets transplanted into an immunodeficient mouse model that allows for in vivo study of xenotransplanted human islets. 2) Determine if GLP-1 administration increases or sustains islet mass in a non-human primate model of islet transplantation. 3) Determine the optimal parameters for GLP-1 administration in a non-human primate model of islet transplantation. As multiple GLP-1 analogues are in clinical trials for the treatment of diabetes, we anticipate that information from these models will be directly relevant and quickly applicable to islet transplantation in humans and should lead to a new approach to increase or sustain islet mass after transplantation.